Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release

Izabela Komarowska, David Coe, Guosu Wang, Robert Haas, Claudio Mauro, Madhav Kishore, Dianne Cooper, Suchita Nadkarni, Hongmei Fu, Daniel A. Steinbruchel, Costantino Pitzalis, Graham Anderson, Pat Bucy, Giovanna Lombardi, Ross Breckenridge, Federica M. Marelli-Berg*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    79 Citations (Scopus)

    Abstract

    Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory Tcells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs Tcell cardiotropism, which was associated with a specialized homing "signature" (c-Met<sup>+</sup>CCR4<sup>+</sup>CXCR3<sup>+</sup>). c-Met signals facilitated Tcell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic Tcell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during Tcell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive Tcells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.

    Original languageEnglish
    Pages (from-to)1087-1099
    Number of pages13
    JournalImmunity
    Volume42
    Issue number6
    Early online date9 Jun 2015
    DOIs
    Publication statusPublished - 16 Jun 2015

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